PMID- 33227945
OWN - NLM
STAT- MEDLINE
DCOM- 20210906
LR  - 20210906
IS  - 2218-273X (Electronic)
IS  - 2218-273X (Linking)
VI  - 10
IP  - 11
DP  - 2020 Nov 19
TI  - Identification and Validation of Carbonic Anhydrase II as the First Target of the 
      Anti-Inflammatory Drug Actarit.
LID - 10.3390/biom10111570 [doi]
LID - 1570
AB  - Background and purpose: Identifying the macromolecular targets of drug molecules 
      is a fundamental aspect of drug discovery and pharmacology. Several drugs remain 
      without known targets (orphan) despite large-scale in silico and in vitro target 
      prediction efforts. Ligand-centric chemical-similarity-based methods for in 
      silico target prediction have been found to be particularly powerful, but the 
      question remains of whether they are able to discover targets for target-orphan 
      drugs. Experimental Approach: We used one of these in silico methods to carry out 
      a target prediction analysis for two orphan drugs: actarit and malotilate. The 
      top target predicted for each drug was carbonic anhydrase II (CAII). Each drug 
      was therefore quantitatively evaluated for CAII inhibition to validate these two 
      prospective predictions. Key Results: Actarit showed in vitro 
      concentration-dependent inhibition of CAII activity with submicromolar potency 
      (IC(50) = 422 nM) whilst no consistent inhibition was observed for malotilate. 
      Among the other 25 targets predicted for actarit, RORgamma (RAR-related orphan 
      receptor-gamma) is promising in that it is strongly related to actarit's 
      indication, rheumatoid arthritis (RA). Conclusion and Implications: This study is 
      a proof-of-concept of the utility of MolTarPred for the fast and cost-effective 
      identification of targets of orphan drugs. Furthermore, the mechanism of action 
      of actarit as an anti-RA agent can now be re-examined from a CAII-inhibitor 
      perspective, given existing relationships between this target and RA. Moreover, 
      the confirmed CAII-actarit association supports investigating the repositioning 
      of actarit on other CAII-linked indications (e.g., hypertension, epilepsy, 
      migraine, anemia and bone, eye and cardiac disorders).
FAU - Ghislat, Ghita
AU  - Ghislat G
AD  - Centre d'Immunologie de Marseille-Luminy, Inserm, U1104, CNRS UMR7280, F-13288 
      Marseille, France.
FAU - Rahman, Taufiq
AU  - Rahman T
AUID- ORCID: 0000-0003-3830-5160
AD  - Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
FAU - Ballester, Pedro J
AU  - Ballester PJ
AD  - Centre de Recherche en Cancerologie de Marseille (CRCM), Inserm, U1068, F-13009 
      Marseille, France.
AD  - CNRS, UMR7258, F-13009 Marseille, France.
AD  - Institut Paoli-Calmettes, F-13009 Marseille, France.
AD  - Aix-Marseille University, UM 105, F-13284 Marseille, France.
LA  - eng
PT  - Journal Article
DEP - 20201119
PL  - Switzerland
TA  - Biomolecules
JT  - Biomolecules
JID - 101596414
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Antirheumatic Agents)
RN  - 0 (Phenylacetates)
RN  - 18699-02-0 (4-(acetylamino)benzeneacetic acid)
RN  - EC 4.2.1.- (Carbonic Anhydrase II)
SB  - IM
MH  - Anti-Inflammatory Agents/*administration & dosage
MH  - Antirheumatic Agents/*administration & dosage
MH  - Arthritis, Rheumatoid/drug therapy/enzymology
MH  - Carbonic Anhydrase II/*antagonists & inhibitors/*metabolism
MH  - Dose-Response Relationship, Drug
MH  - Drug Delivery Systems/methods
MH  - Humans
MH  - Phenylacetates/*administration & dosage
MH  - *Proof of Concept Study
MH  - Reproducibility of Results
PMC - PMC7699199
OTO - NOTNLM
OT  - MolTarPred
OT  - actarit
OT  - carbonic anhydrase II
OT  - malotilate
OT  - target prediction
COIS- The authors declare no conflict of interest.
EDAT- 2020/11/25 06:00
MHDA- 2021/09/07 06:00
PMCR- 2020/11/01
CRDT- 2020/11/24 01:06
PHST- 2020/10/26 00:00 [received]
PHST- 2020/11/13 00:00 [revised]
PHST- 2020/11/16 00:00 [accepted]
PHST- 2020/11/24 01:06 [entrez]
PHST- 2020/11/25 06:00 [pubmed]
PHST- 2021/09/07 06:00 [medline]
PHST- 2020/11/01 00:00 [pmc-release]
AID - biom10111570 [pii]
AID - biomolecules-10-01570 [pii]
AID - 10.3390/biom10111570 [doi]
PST - epublish
SO  - Biomolecules. 2020 Nov 19;10(11):1570. doi: 10.3390/biom10111570.